Local Administration of FK506 with Impregnated Nerve Wraps Accelerates Nerve Regeneration
Joshua M. Barnett, BS1, Bo Xiao, BS1, Yolandi van der Merwe, BS2, Xinzhu Gu, PhD3, Firuz Feturi, BS1, Evan Katzel, MD1, Raman Venkataramanan, PhD4, Mario Solari, MD1, William Wagner, PhD3, Daniel Simons, PhD1, Michael B. Steketee, PhD2, Kia M. Washington, MD1.
1University of Pittsburgh School of Medicine, Pittsburgh, PA, USA, 2University of Pittsburgh, Pittsburgh, PA, USA, 3McGowan Institute for Regenerative Medicine, Pittsburgh, PA, USA, 4University of Pittsburgh School of Pharmacy, Pittsburgh, PA, USA.
Peripheral nerve injuries can be devastating, leading to permanent functional disabilities. Systemic FK506 administration has been shown to hasten recovery and improve functional outcomes after nerve injury repair. However, high systemic levels of FK506 can result in adverse side-effects. Localized administration of FK506 could provide the neuroregenerative benefits of FK506 while avoiding systemic, off-target side-effects. The purpose of this study is to infestigate the utility of a novel FK506-impregnated nerve wrap in treating peripheral nerve injuries in a previously validated rat infraorbital nerve transection and repair model.
Infraorbital nerve transection surgeries were performed on two groups (n=5 per group) of adult Lewis rats. In both groups, the infraorbital branch of the trigeminal nerve was transected. The transected nerve was then repaired primarily with 10-0 nylon suture with (treatment group) or without (no treatment group) the addition of a Poly(ester urethane) urea (PEUU) wrap impregnated with 20 mg of FK506. To evaluate neuroregeneration, trigeminal ganglion cell recordings, objective sensory testing, directional sensitivity, maximal response, and receptor compositions were analyzed from five rats in each group at four and six weeks postoperatively. Recordings from the trigeminal ganglion in na´ve rats were taken for comparison. To assess local FK506 administration, blood and tissue samples (infraorbital nerve, muscle) were analyzed for FK506 concentration using liquid chromatography-mass spectrometry at four and six weeks postoperatively in the treatment group.
Data were analyzed using custom software written in Excel Visual Basic and the Excel add-on statistical package, Analyze-it (Analyse-it Software, LTD). Peristimulus time histograms (PSTHs) having 1 ms bins were constructed from spike times of individual single units. Responses to stimulus onsets (ON responses) were calculated during a 20 ms period beginning 1 ms after deflection onset; this epoch captures the initial, transient phase of the whisker evoked response. Rats within the treatment group (FK506 wraps) were found to have increased response magnitude at 4 weeks after implantation in the infraorbital cut and repair model in comparison to no treatment group (p<.013, Fig. 1). FK506 blood levels at 4 and 6 weeks were close to the limit of quantification (<2ng/ml), whereas concentration within the tissues of interest, the infraorbital nerve and muscle, were much higher.
This study investigates the use of an FK506-impregnated PEUU nerve wrap to improve functional recovery following peripheral nerve injury. Sensory testing provides objective data on the effects of these wraps in the treatment of peripheral nerve injuries and the FK wraps appear to accelerate nerve recovery at 4 weeks, with minimal systemic drug exposure. The findings from this study may translate into novel treatment systems and protocols to treat nerve injuries.
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